The invention relates to the combination of inhibitors of the sodium/hydrogen exchanger with other substances having cardiovascular activity for treating cardiovascular diseases.
Over the last years, inhibitors of the sodium/hydrogen exchanger (NHE) have been characterized in numerous preclinical studies as substances which, in cases of heart hypoperfusion, are suitable in a superior manner for preventing the destruction of the heart tissue at risk. The protection of the heart tissue by NHE inhibitors includes all manifestations of the damage caused by hypoperfusion, from arrhythmia, hypercontraction of the heart muscle and temporary loss of function up to necrosis of heart tissue and associated permanent damage.
The mechanism of action of the NHE inhibitors consists in a reduction of the increased sodium ion influx which is caused in hypoperfused tissues due to intracellular acidification and subsequent activation of the NHE. This results in a delay of the sodium overload of the tissue. Since sodium arm calcium ion transport are coupled in heart tissue, this also prevents the life-threatening calcium overload of the heart cells. This unique mechanism of action of the NHE inhibitors makes it possible to combine them in an advantageous manner with active compounds which are used for treating various cardiovascular diseases and whose cardiovascular action is based on a variety of mechanisms of action.
These combinations of an NHE inhibitor may comprise one or more active components having therapeutic vascular action. The combination of the heart-protecting properties with known therapies of cardiovascular diseases leads on the one hand to an improvement in the quality of the treatment and on the other hand in a large number of combinations to an additive or potentiated increase of the cardiovascular effects of the individual active components. In this context, the mechanistical prevention of sodium overload of the heart cells by the NHE inhibitors is particularly advantageous for the success of the treatment with the combination partner having cardiovascular activity.
The active compounds which are known and identified as NHE inhibitors are guanidine derivatives, preferably acylguanidines, inter alia such as described in the following publications and patent disclosures: Edward J. Cragoe, Jr., xe2x80x9cDIURETICS, Chemistry, Pharmacology and Medicinexe2x80x9d, J. WILEY and Sons (1983), 303-341, additionally compounds of the following formulae: